This invention relates to a process for preparing methyl 3,4,5-trimethoxybenzoate from hydrolyzable tannin and to a process for preparing 3,4,5-trimethoxybenzoic acid via preparation of such methyl ester.
3,4,5-Trimethoxybenzoic acid (hereinafter sometime referred to as "TMB-acid") is useful for preparing pharmaceutical compositions, e.g., trimethoprim. Heretofore, TMB-acid has been prepared by a multiplicity of steps including (1) hydrolyzing tannin or a tannin-containing material to form gallic acid; (2) isolating the gallic acid; (3) methylating the isolated gallic acid to form a mixture of TMB-acid and its methyl ester; (4) saponifying the acid-ester mixture; (5) acidifying the saponified mixture to liberate TMB-acid from its salt; and (6) recovering the TMB-acid. Steps (1) and (2) involving tannin hydrolysis and gallic acid isolation are described in Krueger et al., U.S. Pat. No. 2,732,992. Japanese Pat. No. 56-123938 indicates that methylation of gallic acid and one or more of the remaining steps are described in Org. Syn. Coll., Vol. I, 537, Corriere Favm., 22, 196 (1967). The foregoing highly multiple step process suffers a number of drawbacks, including need for isolation of gallic acid, high cost, and long reaction time where the tannin is hydrolyzed to gallic acid under acid hydrolysis conditions and decomposition of gallic acid to pyrogallic acid where such tannin hydrolysis is effected under alkaline conditions. Accordingly, there is a substantial need in the art for improved processes for preparing TMB-acid and related TMB compounds.
It has now been found that TMB-acid and the methyl ester thereof can be formed by an improved process which obviates the need for hydrolyzing tannin to gallic acid and isolating intermediates.